The invention relates to methods of reducing tissue damage resulting from ischemia using a combination, or a pharmaceutical composition of such combination, of a sodium/hydrogen exchange type-1 (NHE-1) inhibitor and a second compound selected from the group consisting of: (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator. The invention further provides kits directed to such combinations.
Ischemic injury, particularly to that of the myocardium, can occur in out patients as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction, or congestive heart failure. There is currently an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such therapy is anticipated to be life-saving and reduce the need for hospitalization, enhance quality of life and reduce overall health care costs of high risk patients.
Pharmacological cardioprotection would reduce the incidence and progression of myocardial infarction and dysfunction occurring in these perioperative surgical settings. In addition to reducing myocardial damage and improving postischemic myocardial function in patients with ischemic heart disease, cardioprotection would also decrease the incidence of cardiac morbidity and mortality due to myocardial infarction and dysfunction in xe2x80x9cat riskxe2x80x9d patients (i.e., those patients greater than 65 years of age, exercise intolerant, those suffering from coronary artery disease, diabetes mellitus, or hypertension, and the like) that require non-cardiac surgery.
In response thereto, numerous therapeutic regimens have been developed, for example, the use of compounds that inhibit the sodium/hydrogen exchange type-1 (NHE-1) transport system. The mechanism by which NHE-1 inhibitors elicit protective effects against ischemia, particularly that affecting the myocardium, consists of a reduction in the increased sodium ion influx which is caused in reperfused/hypoperfused tissues due to intracellular acidification and subsequent activation of the sodium/hydrogen exchange transport system. This results in a delay of sodium overload of the tissue. Since sodium and calcium ion transport are coupled in cardiac tissue, this also prevents the life-threatening calcium overload of myocardial cells.
The use of NHE-1 inhibitors in combination with certain other therapeutic agents is generally known. For example, EPO 0 918 515 discloses the use of NHE-1 inhibitors with blood pressure reducing agents, ACE-inhibitors, angiotensin receptors antagonists, fat level reducing agents, and HMG-CoA reductase inhibitors; CA 2,227,112 discloses the use of NHE-1 inhibitors with sodium-dependent bicarbonate/chloride exchanger (NCBE) inhibitors; CA 2,245,776 discloses the use of NHE-1 inhibitors with, inter alia, xcex2-receptor blockers, calcium antagonists, loop diuretics, thiazide diuretics, potassium-sparing diuretics, aldosterone antagonists, cardiac glycosides, antiarrythmics, KATP channel openers, KATP channel blockers, and veratride-activatable sodium channel inhibitors; and commonly assigned PCT International Application Publication No. WO 99/43663 discloses the use of NHE-1 inhibitors with, inter alia, adenosine, adenosine agonists, nitrates, platelet inhibitors, aspirin, dipyridamol, potassium chloride, clonidine, prazosin, and adenosine A3-receptor agonists.
In accordance with the practice of the kits, methods and pharmaceutical compositions of the instant invention, it is believed that the administration of a combination of an NHE-1 inhibitor and a second compound selected from the group consisting of: (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator selected from the group consisting of a protein kinase C activator, an endothelin converting enzyme inhibitor, a tissue-activated fibrinolytic inhibitor (TAFI), a Na+/Ca+2 exchanger isoform-1 (NCX-1) inhibitor, and a poly (ADP ribose) synthetase (PARS/PARP) inhibitor, will afford greater therapeutic advantages than either of the combination components administered alone.
The invention provdes methods of reducing tissue damage resulting from ischemia which comprise administering to a mammal in need of such reduction an effective amount of a combination, or a pharmaceutical composition comprising such combination, of an NHE-1 inhibitor and a second compound selected from the group consisting of: (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator.
The invention further provides pharmaceutical compositions comprising an amount of an NHE-1 inhibitor; an amount of a second compound selected from the group consisting of (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator selected from the group consisting of a protein kinase C activator, an endothelin converting enzyme inhibitor, a tissue-activated fibrinolytic inhibitor (TAFI), a Na+/Ca+2 exchanger isoform-1 (NCX-1) inhibitor, and a poly (ADP ribose) synthetase (PARS/PARP) inhibitor; and, preferably, a pharmaceutically acceptable pharmaceutically acceptable carrier, vehicle, or diluent.
The invention further provides a kit comprising an amount of a sodium-hydrogen exchanger type-1 inhibitor, and a pharmaceutically acceptable carrier, vehicle, or diluent in a first unit dosage form; an amount of a second compound selected from the group consisting of (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator selected from the group consisting of a protein kinase C activator, an endothelin converting enzyme inhibitor, a tissue-activated fibrinolytic inhibitor (TAFI), a Na+/Ca+2 exchanger isoform-1 (NCX-1) inhibitor, and a poly (ADP ribose) synthetase (PARS/PARP) inhibitor, and a pharmaceutically acceptable carrier, vehicle, or diluent in a second unit dosage form; and a container.